Chaperones Hsp70 and Hsp40 suppress aggregate formation and apoptosis in cultured neuronal cells expressing truncated androgen receptor protein with expanded polyglutamine tract.

Abstract

Spinal and bulbar muscular atrophy (SBMA) is one of a group of human inherited neurodegenerative diseases caused by polyglutamine expansion. We have previously demonstrated that the SBMA gene product, the androgen receptor protein, is toxic and aggregates when truncated. Heat shock proteins function as molecular chaperones, which recognize and renaturate misfolded protein (aggregate). We thus assessed the effect of a variety of chaperones in a cultured neuronal cell model of SBMA. Overexpression of chaperones reduces aggregate formation and suppresses apoptosis in a cultured neuronal cell model of SBMA to differing degrees depending on the chaperones and their combinations. Combination of Hsp70 and Hsp40 was the most effective among the chaperones in reducing aggregate formation and providing cellular protection, reflecting that Hsp70 and Hsp40 act together in chaperoning mutant and disabled proteins. Although Hdj2/Hsdj chaperone has been previously reported to suppress expanded polyglutamine tract-formed aggregate, Hsdj/Hdj2 showed little effect in our system. These findings indicate that chaperones may be one of the key factors in the developing of CAG repeat disease and suggested that increasing expression level or enhancing the function of chaperones will provide an avenue for the treatment of CAG repeat disease.

• Authors: Y Kobayashi, A Kume, M Li, M Doyu, M Hata, K Ohtsuka, G Sobue
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 275 Issue 12 Pg. 8772-8 (Mar 24 2000) ISSN: 0021-9258 [Print] United States
• PMID: 10722721 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HSP40 Heat-Shock Proteins
• HSP70 Heat-Shock Proteins
• Heat-Shock Proteins
• Molecular Chaperones
• Receptors, Androgen
• Recombinant Proteins
• Polyglutamic Acid

Topics

• Apoptosis
• Cells, Cultured
• HSP40 Heat-Shock Proteins
• HSP70 Heat-Shock Proteins (genetics, metabolism)
• Heat-Shock Proteins (genetics, metabolism)
• In Situ Nick-End Labeling
• Molecular Chaperones (genetics, metabolism)
• Muscular Atrophy, Spinal (genetics)
• Neurons (pathology)
• Polyglutamic Acid (genetics, metabolism)
• Receptors, Androgen (genetics, metabolism)
• Recombinant Proteins (metabolism)
• Trinucleotide Repeats